Discussion
HSCNEC is a rare and clinically challenging malignancy. The first case reported by the present study involved a 76-year-old male patient who was admitted due to intermittent right upper abdominal pain for three months. The patient had a 50-year history of hepatitis B and multiple other chronic health issues, leading to a complex clinical presentation. Intermittent right upper abdominal pain was the initial symptom, and examinations revealed a liver mass and a lesion in the left lung. Based on history, clinical manifestations, examination results and pathology findings, the patient was ultimately diagnosed with HSCNEC. Considering the patient's age, medical history and the extent of the disease, the treatment strategy focused on alleviating symptoms and improving quality of life. However, after undergoing TACE treatment, the patient and the patient's family declined further targeted immunotherapy, and the patient passed away three months later.
The second patient had a history of hepatitis B for >10 years, with elevated AFP levels. A biopsy of the liver mass was performed under ultrasound guidance, revealing SCNEC in segment S8 and HCC in segment S5. Combined with specific pathological immunohistochemical findings, the diagnosis was established as HSCNEC accompanied by HCC. The patient received a comprehensive treatment regimen of TACE combined with sorafenib and tislelizumab, a programmed cell death 1 (PD-1) immune checkpoint inhibitor. Since admission, the patient's tumor size had gradually decreased and stabilized, and tumor marker levels showed a downward trend, with no significant adverse reactions observed during treatment. The patient is currently under regular follow-up.
Both patients underwent ultrasound-guided biopsy of the liver masses and the pathological examination confirmed the presence of SCNEC in the liver. The immunohistochemical profiles (e.g., Synaptophysin+, Chromogranin A+, CD56+) supported neuroendocrine differentiation.
In Case 1, the immunohistochemical profile included chromogranin A (+), synaptophysin (+) and CD56 (+), all of which are established and highly specific markers for neuroendocrine differentiation. The positivity for these markers, along with the characteristic small cell morphology and high Ki-67 index (~70%), strongly supports the diagnosis of SCNEC. While analyses for pro-gastrin-releasing peptide, neuron-specific enolase and insulinoma-associated protein 1 were not routinely performed in this case, their absence does not undermine the diagnostic certainty, as the combination of chromogranin A, synaptophysin and CD56 is widely regarded as sufficient for diagnosing SCNEC in clinical and pathological practice (2). Furthermore, TTF-1 positivity (as reported) is also frequently associated with a small cell morphology and further supports the diagnosis (6).
In Case 2, the patient had a concurrent HCC component in segment S5, which was confirmed by biopsy and immunohistochemistry (arginase-1+, HepPar-1+). The small cell neuroendocrine component (in segment S8) was AFP-negative on immunohistochemistry, indicating that the elevated serum AFP was attributable to the HCC component rather than the NEC. This dual pathology-HSCNEC coexisting with HCC-is rare but documented in the literature (7) and underscores the importance of comprehensive sampling and immunohistochemical profiling. The diagnosis of HSCNEC in this case was based on the immunohistochemistry results of the S8 lesion, which showed strong positivity for synaptophysin, chromogranin A and CD56, and a high Ki-67 index (~70%), consistent with high-grade NEC. The imaging changes in the pancreatic region were considered nonspecific and possibly related to metastasis rather than a primary pancreatic tumor. The patient also had a concurrent HCC in segment S5, further supporting the liver as the primary site of pathology.
In both cases, the treatment strategy was tailored to the dominant hepatic disease. The management of hepatitis B virus (HBV) was a cornerstone of the present therapeutic strategy, particularly for the second patient who received combined therapy. As documented in the case report, this patient had a high viral load at admission (5.35×105 IU/ml). Potent antiviral therapy was initiated and maintained throughout the patient's treatment course. This prophylactic measure was crucial to prevent HBV reactivation-a known risk associated with immune checkpoint inhibitors (8)- and to safeguard liver function during repeated TACE sessions. The successful prevention of reactivation and the maintenance of stable liver function were fundamental enablers, allowing the patient to safely complete multiple cycles of TACE combined with sorafenib and camrelizumab.
While the direct role of HBV in the oncogenesis of HSCNEC itself is not well-defined, its presence significantly shaped the management plan in the present study. The contrasting outcomes of the two cases powerfully highlight the critical importance of the comprehensive treatment regimen. The first patient, who received only TACE and declined further targeted immunotherapy, succumbed to the disease rapidly. In stark contrast, the second patient, under the protective cover of antiviral therapy, successfully received the full combination of TACE, targeted therapy and immunotherapy. It is this specific and safely administered combination that was instrumental in achieving tumor control, reduction in tumor markers and the remarkable improvement in the patient's quality of life and overall survival.
HSCNEC is a rare intrahepatic neuroendocrine tumor. Surgery is the primary potential treatment option, aimed at directly removing tumor tissue and reducing the tumor burden. However, patients must meet specific surgical criteria to be eligible for this intervention. For localized NEC classified as stage I to III according to the clinical staging of liver cancer in China, the five-year overall survival rate after surgery is only 25 to 40% (9). However, not all patients are suitable for surgical resection, particularly those with unfavorable tumor locations, multiple tumors or distant metastases. Research has shown that the intrinsic histopathological features of the tumor (its composition, including differentiation grade, histological subtype and the presence of mixed components), lymph node involvement, distant metastasis and clinical staging are significant factors influencing patient prognosis (7). The pathogenesis of HSCNEC differs from that of traditional liver cancer and is often accompanied by multiple metastases, leading to varied responses to existing treatment modalities. Consequently, TACE alone often has limited efficacy, necessitating treatment strategies that are tailored to the patient's individual condition, tumor biology and overall health status. Combining targeted therapies with immunotherapy can provide a more precise treatment approach, enhancing the effectiveness of tumor management. Clinical applications have demonstrated certain efficacy and advantages in this context.
TACE is an interventional treatment technique that is widely used in the management of liver tumors (10,11). TACE involves the direct injection of chemotherapy drugs into the hepatic artery supplying the tumor, utilizing local chemotherapy and embolization to obstruct the tumor's blood supply, thereby controlling tumor growth. The advantages of TACE include its minimally invasive nature, good operability and relatively low risk, which can contribute to extending patients' survival. However, TACE is not without its limitations. Post-treatment, there often remains a histological level of tumor tissue that is not completely necrotic, increasing the risk of tumor recurrence. Additionally, repeated TACE treatments can significantly impair liver function, particularly in cases of large HCC or massive liver tumors. The tumor microenvironment may also change following TACE, potentially promoting immune evasion, where tumor cells can utilize various mechanisms to reduce the immune system's ability to recognize and attack them. TACE often struggles to ensure complete necrosis of tumor tissue (10), and for certain patients, tumor recurrence can occur after treatment (12). To enhance the efficacy of TACE and reduce the risk of distant metastasis, early combination with targeted molecular therapies should be considered (12,13). Currently, the combination of TACE with targeted molecular therapies has shown superior efficacy compared to the use of targeted therapies alone (14,15). In recent years, there have been increasing explorations of combining targeted therapies with immunotherapy.
Targeted therapy primarily focuses on specific molecular markers unique to tumor cells, inhibiting their proliferation and metastasis by blocking particular signaling pathways or molecular targets. This approach effectively attacks tumor cells while minimizing damage to normal cells (16). By contrast, immunotherapy works by activating or enhancing the patient's own immune system to recognize and eliminate tumor cells (17).
The application of TACE in combination with targeted and immunotherapy can attack tumor cells on multiple levels: TACE directly destroys tumor cells, while targeted therapies address the specific molecular alterations in these cells, obstructing pathways that promote tumor growth and spread. Furthermore, in certain cases, the combination of targeted therapy and immunotherapy can produce synergistic effects, enhancing the body's ability to eliminate tumors. Given their distinct mechanisms, the combination of TACE with targeted and immunotherapy can extend the survival of patients with advanced liver cancer, demonstrating superior efficacy compared to TACE alone (5,18,19). This synergistic approach can lead to improved overall treatment outcomes. When TACE is combined with targeted immunotherapy, the advantages of both approaches are integrated, allowing for complementary benefits. This combination enables local control of the tumor, as well as a systemic immune response. The use of TACE in conjunction with PD-1/PD-L1 inhibitors and targeted therapies has shown significant advantages in progression-free survival, overall survival and objective response rates in patients with advanced liver cancer (5). In clinical practice, the combination of TACE with targeted immunotherapy offers patients a more personalized treatment approach. By analyzing the molecular and biological characteristics of the tumor, suitable targeted therapies can be selected, alongside immune checkpoint inhibitors and other immunotherapeutic agents, to enhance the comprehensiveness and depth of treatment. This integrated treatment model helps to overcome the limitations of single-modality therapies and improves therapeutic efficacy (20).
The advantages of combining TACE with targeted immunotherapy are also evident in treatment outcomes. This comprehensive approach can significantly enhance treatment effectiveness, prolonging both progression-free survival and overall survival for patients. Additionally, combination therapy can improve patients' quality of life, reduce adverse reactions during treatment, lower recurrence rates and ultimately improve patient prognosis (21). However, the combination of TACE with targeted immunotherapy also faces challenges. This approach may lead to more severe adverse effects (22–24), which can vary from person to person. In cases where adverse effects occur, treatment can be paused for observation and symptomatic supportive care can be provided. Furthermore, selecting the appropriate targeted immunotherapy agents, determining the optimal treatment combinations, monitoring treatment responses and managing potential adverse reactions all require ongoing optimization and standardization through clinical trials and practice. Finally, due to the heterogeneity of hepatocellular NEC, its response to the combination of TACE and targeted immunotherapy may differ from that of traditional HCC, necessitating further research to explore these differences.
In conclusion, HSCNEC is a rare intrahepatic neuroendocrine tumor and its etiology remains unclear. Preoperative imaging diagnosis primarily relies on enhanced CT and MRI, while definitive diagnosis requires biopsy of the tumor for pathological assessment (11). Radical surgical resection is the preferred treatment option (9), and for patients who are not candidates for surgery, TACE combined with targeted immunotherapy can be considered (5). This multimodal approach can significantly enhance treatment efficacy, prolong overall survival, improve quality of life, reduce treatment-related adverse events, lower recurrence rates and ultimately improve prognosis (5,21). Additionally, regular follow-up is essential after comprehensive treatment (11).